Graft-versus-host disease (GVHD) is caused by orchestrated host-reactive donor T cell responses and remains a major complication of allogeneic bone marrow transplantation (BMT) or hematopoietic stem cell transplantation. Although GVHD can be attenuated by global suppression of T cell immunity or donor T cell depletion, these treatments also abrogates beneficial donor T cell responses against residual tumors or infectious pathogens. Our long-term goal is to seek the methods for immunological intervention that selectively inhibits GVHD while sparing T cell responses to cancers and pathogens. Our preliminary data demonstrate that LIGHT-HVEM is a potent co-stimulatory pathway which is prerequisite for the generation of GVHD. Abrogation of LIGHT-HVEM signal inhibits the generation of allo-reactive CTL in parent into F1 transplantation mouse GVHD model, whereas it does not impair vaccine-induced CTL responses to nominal antigens. The central hypothesis of this proposal is that blockade of LIGHT-HVEM pathway can prevent GVHD without a global immune suppression. Therefore, this approach will be developed to treat clinical GVHD and to maintain graft-versus-leukemia (GVL) effect. To test this hypothesis, we will first establish LIGHT-HVEM blockade as a efficient immunotherapy for clinically relevant GVHD models such as those induced by MHC-matched, minor histocompatibility Ag-mismatched BMT. Second, functional role of BTLA and LTbR, molecules related with LIGHT-HVEM co-stimulatory pathway, in GVHD will be explored. Finally, combination therapy of LIGHT-HVEM blockade and anti-tumor DC vaccine will be tested to treat GVHD while mediating GVL effects. This study will lay the foundation for the development of LIGHT-HVEM blockade therapy as future clinical applications in GVHD and GVL associated with allogeneic BMT for leukemia patients. Graft-versus-host disease (GVHD) is one of the most life-threatening complications after bone marrow transplantation. In this project, we will discover novel immunological therapies for GVHD through a manipulation of LIGHT, a recent member of co-signal molecule.